Kallistatin, a serine protease inhibitor (PI), inhibits kallikrein and kinin production and growth of human retinal capillary endothelial cells (RCEC). KS levels are decreased in retina, serum and vitreous of Db patients and in STZ-rats. The hypothesis formulated herein is that in diabetes, low KS leads to a weakened growth inhibition of EC in the retina, indirectly enhancing neo-vascularization. Aims are: 1: identify the causes and mechanisms of low KS in DM by testing the effects of high glucose, insulin and hypoxia on KS production in RCEC and hepatocytes, 2: determine if KS effects on cell growth occur via the kallikrein-kinin system or through a KS-specific receptor or other growth factors. These effects will be tested in the presence or absence of a kinin receptor antagonist. KS-R will be defined on RCEC and the effect of KS on the expression of growth factors will be examined. 3: Retinal neovascularization, induced by hyperoxia in KS-transgenic mice will help determine whether overexpression of KS can reduce or prevent retinal NV in these mice. Thus, KS will be examined with respect to its effects as an endothelial growth inhibitor. The mechanisms of KS regulation may provide evidence of new pathogenic factors in DR.